Ocular Phenotype Associated with DYRK1A Variants

G C A T T A C G G C A T genes Article Ocular Phenotype Associated with DYRK1A Variants Cécile Méjécase 1,† , Christopher M. Way 1,†, Nicholas Owen 1 and Mariya Moosajee 1,2,3,4,* 1 UCL Institute of Ophthalmology, London EC1V E9L, UK; [email protected] (C.M.); [email protected] (C.M.W.); [email protected] (N.O.) 2 Moorfields Eye Hospital NHS Foundation Trust, London EC1V 2PD, UK 3 Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK 4 The Francis Crick Institute, London NW1 1AT, UK * Correspondence: [email protected] † These authors are co-first authors. Abstract: Dual-specificity tyrosine phosphorylation-regulated kinase 1A or DYRK1A, contributes to central nervous system development in a dose-sensitive manner. Triallelic DYRK1A is implicated in the neuropathology of Down syndrome, whereas haploinsufficiency causes the rare DYRK1A-related intellectual disability syndrome (also known as mental retardation 7). It is characterised by intellectual disability, autism spectrum disorder and microcephaly with a typical facial gestalt. Preclinical studies elucidate a role for DYRK1A in eye development and case studies have reported associated ocular pathology. In this study families of the DYRK1A Syndrome International Association were asked to self-report any co-existing ocular abnormalities. Twenty-six patients responded but only 14 had molecular confirmation of a DYRK1A pathogenic variant. A further nineteen patients from the UK Genomics England 100,000 Genomes Project were identified and combined with 112 patients reported in the literature for further analysis. Ninety out of 145 patients (62.1%) with heterozygous DYRK1A variants revealed ocular features, these ranged from optic nerve hypoplasia (13%, 12/90), refractive error (35.6%, 32/90) and strabismus (21.1%, 19/90). Patients with DYRK1A variants should be referred to ophthalmology as part of their management care pathway to prevent amblyopia in Citation: Méjécase, C.; Way, C.M.; children and reduce visual comorbidity, which may further impact on learning, behaviour, and Owen, N.; Moosajee, M. Ocular quality of life. Phenotype Associated with DYRK1A Variants. Genes 2021, 12, 234. Keywords: DYRK1A; DYRK1A-related intellectual disability syndrome; mental retardation 7; ocular https://doi.org/10.3390/ phenotype; optic nerve hypoplasia; strabismus and refractive error genes12020234 Academic Editor: Paul Sieving Received: 20 January 2021 Accepted: 29 January 2021 1. Introduction Published: 5 February 2021 DYRK1A is composed of 13 exons, which encode the 763 amino acid dual-specificity tyrosine phosphorylation-regulated kinase 1A, or DYRK1A protein. This proline directed Publisher’s Note: MDPI stays neutral kinase is part of the DYRK family of five members (DYRK1A, DYRK1B, DYRK2, DYRK3 with regard to jurisdictional claims in and DYRK4). It is highly expressed in the developing and adult central nervous system published maps and institutional affil- (CNS) [1,2]. Once activated by auto-phosphorylation [3], it phosphorylates serine or threo- iations. nine residues of transcription, splicing, synaptic, apoptotic and translocation factors [4,5] to influence neurogenesis, neural differentiation, synaptic function and apoptotic pathways [5]. Within the CNS, DYRK1A is involved in dendritic arborization [6–8], cell cycle control, neural development and axon growth through interactions with various processes Copyright: © 2021 by the authors. such as the nuclear factor of activated T-cells (NFAT) and cAMP response-element binding Licensee MDPI, Basel, Switzerland. (CREB) pathways [6,9–11]. This article is an open access article DYRK1A is located on chromosome 21q22.13 within the critical region causing Down distributed under the terms and syndrome (also known as Trisomy 21). Overexpression of DYRK1A produces similar neurode- conditions of the Creative Commons velopmental [12–14] and neurodegenerative [15–17] changes to animal disease models with Attribution (CC BY) license (https:// Down syndrome. Haploinsufficiency of DYRK1A through chromosomal loss of heterozy- creativecommons.org/licenses/by/ gosity, microdeletions or intragenic mutation causes the rare DYRK1A-related intellectual 4.0/). Genes 2021, 12, 234. https://doi.org/10.3390/genes12020234 https://www.mdpi.com/journal/genes Genes 2021, 12, 234 2 of 14 disability syndrome, which was first detected through karyotype analysis of partial mono- somy of chromosome 21 [18–20]. Comparative genomic hybridization has since allowed the discovery of a number of cases of chromosome 21 microdeletions, and the syndrome was termed autosomal dominant mental retardation 7 (MRD7, MIM#614104) [21–26]. Next- generation sequencing has allowed the identification of numerous point and frameshift variants in DYRK1A [27–31]. DYRK1A-related intellectual disability syndrome is characterised by a broad syn- dromic phenotype. It has a particular facial gestalt of deep-set eyes, short nose with a broad tip, up-slanting palpebral fissures, turned down corners of the mouth, dysplastic ears and retrognathia with a broad chin. Hand and foot abnormalities include long tapered fingers, small hands and feet, toe syndactyly and high arched feet [32]. These features may not be seen until adulthood [22]. Microcephaly and moderate intellectual deficit are observed in 80% of cases, with the remaining 20% suffering from mild intellectual deficit. Other findings include psychomotor delay, febrile seizures, anxiety, altered stress reactions [22], spinal and thoracic features (including pectus excavatum, kyphosis and scoliosis) [32], gastrointestinal features (including feeding difficulties and gastroesophageal reflux) [32], cardiac features (including ventricular septal defect, patent ductus arteriosus, aortic valve disease), as well as renal features (agenesis and renal cysts) [32]. Animal models of DYRK1A haploinsufficiency report structural ocular defects and visual impairment. The optic lobe of mnb Drosophila is disproportionately more reduced than other areas of the brain and is associated with poor functional visual pattern fixa- tion compared to controls [33]. Dyrk1a+/− mice have 25% smaller eyes (microphthalmia), a thinner retina, fewer retinal ganglion cells and altered retinal functioning measured by electroretinography (ERG) [34]. Mice triallelic for Dyrk1a also show poor retino-cortical visual processing and this effect is eliminated when DYRK1A copy number is normalised [35], suggesting the role of DYRK1A in visual system development is dose sensitive. Several individuals with DYRK1A variants have been described with a variety of ocular pathologies [27,30,32,36]. However, it is unclear whether these eye defects are associated with the syndrome or incidental findings. In addition, several of the published case series do not investigate ophthalmic features. In this study, DYRK1A families belonging to the DYRK1A Syndrome International Association (DSIA) were asked to self-report any co-existent ocular disease together with their genetic results. Further patients were identified through the UK Genomics England 100,000 Genomes Project and combined with a review of the literature with the aim to outline the ocular phenotype seen in patients with DYRK1A variants. 2. Materials and Methods This study had relevant local and national research ethics committee approvals (Moorfields Eye Hospital NHS Foundation Trust and the Northwest London Research Ethics Committee) and adhered to the tenets of the Declaration of Helsinki. Patients and relatives gave written informed consent for genetic testing through either the Genetic Study of Inherited Eye Disease (REC reference 12/LO/0141) or Genomics England 100,000 Genomes project (REC reference 14/EE/1112). After consultation with the DYRK1A Syndrome International Association (DSIA), patient families were contacted to request anonymised information about their clinical diagnosis including their genetic result and any recorded ophthalmic phenotype. Guardians of patients provided informed consent. Patients without a confirmed molecular diagnosis were excluded from the analysis of ocular phenotype. Participants of the UK 100,000 Genomes Project underwent whole genome sequence (WGS) analysis [37]. High-throughput sequencing data were aligned to the human genome (GRCh38) using Isaac (Illumina Inc.), single nucleotide variants (SNVs) and indels (inser- tions and deletions) were identified, annotated and filtered using minor allele frequency in public datasets, predicted effect on protein and familial segregation (data release 11). Through the Genomics England data research embassy, variants were prioritised using the Genes 2021, 12, 234 3 of 14 Intellectual Disability virtual gene panel (PanelApp, version 3.2), which includes DYRK1A, and variants identified as pathogenic or likely pathogenic were reported. Classification of such variants were based on the guidelines of the American College of Medical Genetics and Genomics (ACMG) [38]. Ocular features reported using human phenotype ontology (HPO) terms associated with the cases identified were analysed. All HPO terms observed are reported in Supplementary Table S1. A review of the literature was also performed [19,20,22–30,32,39–51]. For each patient, their genetic defect and ocular phenotype was collected. Ocular features were categorised into refractive error, strabismus, enophthalmia (posterior displacement of the eye with sunken appearance), optic nerve abnormalities and other findings (Supplementary Table S2). Patients who unfortunately did not survive the neonatal

Load more